trimethoprim/sulfamethoxazole

Trimethoprim/sulfamethoxazole is a combination antibiotic used to treat or prevent a variety of infections of the urinary, respiratory, and gastrointestinal tracts.

The combination is a broad-spectrum antibiotic with activity against a wide range of bacteria. The two drugs in the formulation block 2 consecutive steps in the synthesis of nucleic acids and proteins essential for bacteria to grow and multiply. Studies suggest bacterial resistance develops more slowly with the use of a combination than only one of the two drugs as monotherapy.

Sulfamethoxazole and trimethoprim inhibit two sequential steps in the synthesis of folic acid, a vital nutrient required for the synthesis of bacterial DNA and RNA. Sulfamethoxazole is a sulfonamide or sulfa drug that inhibits the synthesis of dihydrofolic acid from para-amino-benzoic acid (PABA). Trimethoprim inhibits dihydrofolate reductase, the enzyme required for the production of tetrahydrofolic acid from dihydrofolic acid, the next step in folic acid synthesis.

The uses of trimethoprim/sulfamethoxazole include:

FDA- approved

Adult and Pediatric:

• Urinary tract infections
• Shigellosis
• Pneumocystis jirovecii pneumonia

Adults:

• Chronic bronchitis
• Sepsis
• Traveler’s diarrhea

Pediatric:

• Acute otitis media

Off-label

Adult:

• Bacterial meningitis
• Bartonella spp. Infection
• Prevention or treatment of bite wound infection (animal or human bite)
• Brucellosis
• Cellulitis, recurrent, purulent, or with risk for methicillin-resistant Staphylococcus aureus (MRSA)
• Cyclosporiasis
• Cystoisosporiasis (isosporiasis)
• Diabetic foot infection
• Epididymitis
• Granuloma inguinale (donovanosis)
• Impetigo or ecthyma
• Intra-abdominal infection
• Intracranial abscess (brain abscess, intracranial epidural abscess)
• Spinal epidural abscess (MRSA)
• Lactational mastitis
• Melioidosis (Burkholderia pseudomallei) infection
• Nocardiosis
• Osteomyelitis
• Plague (Yersinia pestis)
• Prostatitis
• Prosthetic joint infection
• Q fever (Coxiella burnetii)
• Septic arthritis (MRSA)
• Prevention of spontaneous bacterial peritonitis
• Stenotrophomonas maltophilia infections
• Surgical prophylaxis
• Toxoplasma gondii encephalitis (prophylaxis/treatment/chronic maintenance) in patients with HIV

Organisms susceptible to trimethoprim/sulfamethoxazole include:

Acinetobacter baumannii, Actinobacillus actinomycetemcomitans, Aeromonas hydrophila, Alcaligenes xylosoxidans, Bartonella henselae, Bordetella pertussis, Brucella spp, Burkholderia pseudomallei, Burkholderia cepacia, Chryseobacterium meningosepticum, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus aphrophilus, Haemophilus influenzae, Hafnia alvei, Kingella spp, Klebsiella pneumoniae, Klebsiella granulomatis, Legionella spp, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, MRSA, MSSA, Nocardia asteroides, Plesiomonas shigelloides, Pneumocystis jiroveci (PCP), Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Salmonella typhi, Serratia spp, Shigella spp, Staphylococcus saprophyticus, Stenotrophomonas maltophilia, Streptococcus pneumoniae, Tropheryma whippelii, Vibrio cholerae, Yersinia enterocolitica, Yersinia pseudotuberculosis, and various Mycobacteria

• Do not use trimethoprim/sulfamethoxazole in patients with:
  • Known hypersensitivity to sulfamethoxazole or any sulfa drug, trimethoprim or any component of the formulation
  • History of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides
  • Megaloblastic anemia due to folate deficiency
  • Significant liver damage
  • Severe kidney insufficiency when kidney function cannot be monitored
• Do not administer trimethoprim/sulfamethoxazole to children younger than 2 months.
• Do not use trimethoprim/sulfamethoxazole concurrently with dofetilide.
• Trimethoprim/sulfamethoxazole can cause fetal harm. Avoid use in pregnant women, unless maternal benefits from treatment outweigh the risks to the fetus. If a patient becomes pregnant during therapy, apprise them of the potential hazard to the fetus. Avoid use in breastfeeding women.
• Severe allergic reactions, sometimes fatal, have occurred with the use of sulfonamide drugs. Discontinue trimethoprim/sulfamethoxazole at the first sign of skin rash or other hypersensitivity reactions.
• There have been severe cases of thrombocytopenia and other blood disorders associated with trimethoprim/sulfamethoxazole treatment. Monitor the patient’s blood count regularly during therapy.
• Avoid the use of trimethoprim/sulfamethoxazole in the treatment of streptococcal pharyngitis, the drug has not been shown to be adequately effective and does not prevent complications such as rheumatic fever.
• As with most antibacterial agents, trimethoprim/sulfamethoxazole use can alter the gut flora and lead to Clostridium difficile overgrowth that can cause pseudomembranous colitis and C. difficile-associated diarrhea (CDAD), even up to two months after discontinuation. Monitor patients for signs of colon inflammation (colitis) and diarrhea, and treat promptly.
• Some formulations of trimethoprim/sulfamethoxazole contain sodium metabisulfate that can cause allergic reactions, including anaphylaxis and severe asthmatic episodes in patients with sulfite sensitivity, seen relatively more often in people with asthma.
• Some formulations contain benzyl alcohol, which is associated with “gasping syndrome” in newborns, which can be fatal. Avoid such formulations in young babies.
• Some formulations contain propylene glycol, which can be toxic in large amounts.
• Avoid coadministration of trimethoprim/sulfamethoxazole and leucovorin during the treatment of Pneumocystis jirovecii pneumonia. Treatment failure and excess mortality were noted in concomitant treatment in patients with HIV in a clinical trial.
• Avoid the use of trimethoprim/sulfamethoxazole in patients with:
  • Impaired kidney or liver function
  • Possible folate deficiency
  • Severe allergies or bronchial asthma
• In patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), an enzyme essential for the normal functioning of red blood cells, trimethoprim/sulfamethoxazole use can lead to hemolytic anemia. Exercise caution.
• There have been reports of hypoglycemia in non-diabetic patients, particularly those receiving high doses of trimethoprim/sulfamethoxazole, and those with kidney dysfunction, liver disease, or malnutrition. Use with caution.
• Trimethoprim can impair the metabolism of phenylalanine, an amino acid.
• Exercise caution to avoid extravasation with an infusion of trimethoprim/sulfamethoxazole.
• Avoid use in hypothyroidism and porphyria, trimethoprim/sulfamethoxazole can precipitate porphyria crisis and hypothyroidism.
• Patients with acquired immunodeficiency syndrome (AIDS) may not respond to or tolerate trimethoprim/sulfamethoxazole therapy. Monitor the patients and reevaluate therapy if the patient develops severe adverse reactions.
• Trimethoprim/sulfamethoxazole therapy may cause electrolyte abnormalities. Monitor patients and ensure adequate fluid intake by the patients.
• Prolonged trimethoprim/sulfamethoxazole use may cause an overgrowth of non-susceptible organisms and result in fungal or bacterial superinfections. In the absence of a proven or strongly suspected bacterial infection or a prophylactic indication, this combo drug is unlikely to be beneficial and increases the risk of the development of drug-resistant bacteria.

Common side effects of trimethoprim/sulfamethoxazole include:

• Abdominal pain
• Loss of appetite (anorexia)
• Nausea
• Vomiting
• Diarrhea
• Sore mouth (stomatitis)
• Tongue inflammation (glossitis)
• Inflammation of the pancreas (pancreatitis)
• Liver inflammation (hepatitis)
• Jaundice from impaired bile flow (cholestatic jaundice)
• Elevation of liver enzymes (transaminases)
• Elevated blood levels of bilirubin (hyperbilirubinemia)
• Destruction of liver cells (hepatic necrosis)
• Allergic skin reactions including:
  • Rash
  • Hives (urticaria)
  • Pruritus (itching)
  • Photosensitivity
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis
  • Erythema multiforme
  • Exfoliative dermatitis
• Hypersensitivity reactions including:
  • Chills
  • Drug fever
  • Swelling beneath the skin and in the mucous tissue (angioedema)
  • Serum-sickness like syndrome
  • Allergic inflammation of heart muscle (allergic pericarditis)
  • Systemic lupus erythematosus (SLE)
  • Red eye (conjunctival and scleral injection)
  • Severe allergic reaction (anaphylaxis)
  • Henoch-Schonlein purpura, a disorder that causes inflammation and bleeding of small blood vessels
  • Periarteritis nodosa, a condition that causes inflammation of small and medium arteries in multiple organs
  • Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Blood disorders including:
  • Severely low count of granulocyte immune cells (agranulocytosis)
  • Low red blood cell (RBC) count due to lack of RBC production (aplastic anemia)
  • Anemia due to rapid destruction of RBCs (hemolytic anemia)
  • Anemia from production of abnormally large RBCs (megaloblastic anemia)
  • Low count of neutrophil immune cells (neutropenia)
  • Low count of leukocyte immune cells (leukopenia)
  • Low platelet levels (thrombocytopenia)
  • Deficiency of prothrombin, a blood-clotting substance (hypoprothrombinemia)
  • Methemoglobinemia, a disorder with excessive methemoglobin, a form of hemoglobin that does not deliver oxygen to the cells
  • High level of eosinophil inflammatory immune cells (eosinophilia)
• Inflammation in the kidney (interstitial nephritis)
• Kidney failure
• Increase in blood urea nitrogen (BUN)
• Elevated creatinine levels
• Kidney injury from drug toxicity (toxic nephrosis)
• Reduced or absent urine production (oliguria or anuria)
• Crystals in urine (crystalluria)
• Excessive urination (diuresis)
• High potassium in the blood (hyperkalemia)
• Low blood sodium level (hyponatremia)
• Cough
• Shortness of breath (dyspnea)
• Lung inflammation from eosinophilia (eosinophilic pneumonitis)
• Pulmonary filtrates
• Pulmonary injury
• Acute respiratory failure
• Vertigo
• Headache
• Convulsions
• Inflammation of the peripheral nerves (peripheral neuritis)
• Aseptic inflammation of the brain and spinal cord membrane (meningitis)
• Impairment of balance, coordination and speech (ataxia)
• Ringing in the ears (tinnitus)
• Inflammation of the eye’s middle layer (uveitis)
• Joint pain (arthralgia)
• Muscle pain (myalgia)
• Breakdown of muscle tissue (rhabdomyolysis)
• Fatigue
• Weakness
• Fever
• Insomnia
• Apathy
• Nervousness
• Depression
• Hallucinations
• Infusion or injection site reactions such as:
  • Pain
  • Irritation
  • Inflammation
• Circulatory shock
• Inflammation with a blood clot in the veins (thrombophlebitis)

Less common side effects of trimethoprim/sulfamethoxazole include:

• C. difficile infection and associated colon inflammation (pseudomembranous enterocolitis)
• Taste disorder (dysgeusia)
• Irregular heart rhythm and abnormal ECG (prolonged QT interval)
• Torsades de pointes, a life-threatening condition causing a rapid heart rate that starts in the ventricles
• Low blood glucose level (hypoglycemia)
• Excessive acidity in the body fluids (metabolic acidosis)
• Idiopathic thrombocytopenic purpura, a condition that causes easy bleeding and bruising because of low platelet levels
• Thrombotic thrombocytopenic purpura, a disorder that causes blood clot formation in small blood vessels all over the body

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Injected Solution

16 mg/80 mg/mL

Oral Suspension

• 40 mg/200 mg/5 mL

Tablet

• 80 mg/400 mg
• 160 mg/800 mg

Adult:

Dosing Guidelines for Infections

• 1-2 DS tablets orally every 12-24 hours
• 8-20 mg trimethoprim (TMP)/kg/day intravenous (IV) every 6-12 hours  

Chronic Bronchitis

Acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae

• DS tablet: 1 orally every 12 hours for 10-14 days

Meningitis, Bacterial

• 10-20 mg TMP/kg/day IV divided every 6-12 hours  

Pneumocystis (Carinii) Jiroveci Pneumonia

• Documented Pneumocystis jiroveci pneumonia (PCP); also, prophylaxis against PCP in individuals who are immunosuppressed

Prophylaxis

• Tablet: 80-160 mg TMP orally once daily or 160 mg TMP 3 times/week on consecutive or alternate days

Treatment

• 15-20 mg TMP/kg/day oral/IV divided every 6-8 hours  

Sepsis

• 20 mg TMP/kg/day IV divided every 6 hours  

Shigellosis

• Enteritis caused by susceptible strains of Shigella flexneri and S. sonnei
• DS tablet: 1 tablet orally every 12 hours for 5 days
• Alternatively, 8-10 mg TMP/kg/day IV divided every 6-12 hours for up to 5 days  

Traveler's Diarrhea

• Traveler's diarrhea due to susceptible strains of enterotoxigenic Escherichia coli
• DS tablet: 1 tablet orally every 12 hours for 5 days

Urinary Tract Infections

• UTIs caused by susceptible strains of Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis, and Proteus vulgaris
• Pyelonephritis: 1 DS tab or 2 regular-strength tabs orally every 12 hours for 14 days
• Prostatitis: 1 DS tab or 2 regular-strength tabs orally every 12 hours for 14 days or 2-3 months if chronic infection
• A 3-to-5-day course may be used for acute, uncomplicated cystitis
• Prophylaxis (off-label): Various regimens exist; may use regular-strength tablet once/twice per week

Acne Vulgaris (Off-label)

• 1 DS tab or 1 regular-strength tab orally once daily or once every 12 hours for up to 18 weeks

Community Acquired Pneumonia (Off-label)

• 1 DS tab orally every 12 hours for 10-14 days

Dosage Modifications

Renal impairment

• Creatinine clearance (CrCl) above 30 mL/min: Dose adjustment not necessary
• CrCl 15-30 mL/min: Decrease dose by 50%
• CrCl <15 mL/min: Do not use

Renal impairment, off-label

• Administer doses oral/IV
• Dosing (Dose based on Total Body Weight (TBW) and trimethoprim component; use TBW in obese patients)
• Pneumocystis jjirovecii pneumonia (PJP) prophylaxis
  • CrCl below 30 mL/min: 160 mg (1DS) every 24 hours or 80 mg (1 SS) every 24 hours or 160 mg (1DS) 3 times a week
  • Hemodialysis (HD): 80 mg (1 SS) every 24 hours or 160 mg (1DS) 3 times a week; on hemodialysis days, administer dose post-HD
  • Continuous renal replacement therapy (CRRT): 160 mg (1 DS) every 24 hours or 80 mg (1SS) every 24 hours or 160 mg (1DS) 3 times a week
• Pneumocystis jjirovecii pneumonia (PJP) treatment
  • CrCl below 30 mL/min: 5 mg/kg every 12 hours
  • HD: 10 mg/kg post-HD
  • CRRT: 5 mg/kg every 12 hours
  • Total daily dose: 15-20 mg/kg/day for Pneumocystis treatment
• Skin and soft tissue infection
  • CrCl below 30 mL/min: 80-160 mg (1-2 SS) every 12 hours
  • HD: 80 mg (1SS) every 24 hours; on hemodialysis days, administer dose post-HD
  • CRRT: 80-160 mg (1-2SS) every 12 hours
• Stenotrophomonas treatment
  • CrCl below 30 mL/min: 4 mg/kg every 12 hours
  • HD: 8 mg/kg post-HD
  • CRRT: 4 mg/kg every 12 hours
  • Total daily dose: 12-15 mg/kg/day for Stenotrophomonas treatment
• Urinary tract infection
  • CrCl below 30 mL/min: 80 mg (1SS) every 12 hours
  • HD: 80 mg (1SS) every 12 hours; on hemodialysis days, administer dose post-HD
  • CRRT: 160 mg (1DS) every 12 hours
• Other Infections
  • CrCl below 30 mL/min: 3 mg/kg every 12 hours
  • HD: 6 mg/kg post-HD
  • CRRT: 3 mg/kg every 12 hours
  • Total daily dose: 8-12 mg/kg/day

Pediatric:

Mild to Moderate Infections

• Children below 2 months: Contraindicated
• Children above 2 months:
  • 8 mg TMP/kg/day orally divided every 12 hours

Serious Infections

• Children below 2 months: Contraindicated
• Children above 2 months:
  • 15-20 mg TMP/kg/day orally divided every 6 hours  
  • 8-12 mg TMP/kg/day IV divided every 6-12 hours

Acute Otitis Media

• Acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae
• Children below 2 months: Contraindicated
• Children above 2 months:
  • 6-10 mg TMP/kg/day orally divided every 12 hours for 10 days  

Pneumocystis (Carinii) Jiroveci Pneumonia

• Children below 2 months: Contraindicated
• Children above 2 months:
  • Treatment: 15-20 mg TMP/kg/day oral/IV divided every 6-8 hours for 21 days  
  • Prophylaxis: 150 mg TMP/m²/day orally divided every 12 hours for 3 days/week on consecutive or alternate days

Shigellosis

• Children below 2 months: Contraindicated
• Children above 2 months:
  • 8 mg TMP/kg/day orally divided every 12 hours for 5 days  
  • 8-10 mg TMP/kg/day IV divided every 6-12 hours for 5 days

Urinary Tract Infection

• Children below 2 months: Contraindicated
• Children above 2 months:
  • 8 mg TMP/kg/day orally divided every 12 hours for 7-14 days if serious infection  
  • 8-10 mg TMP/kg/day IV divided every 6-12 hours for 14 days if serious infection
  • Prophylaxis: 2 mg TMP/kg/dose orally once daily or 5 mg TMP/kg/dose twice weekly

Skin/soft Tissue Infection Due to Community Acquired MRSA (Off-label)

• 8-12 mg TMP/kg/day orally divided every 12 hours for 5-10 days; add beta-lactam antibiotic to the regimen if beta-hemolytic Streptococcus spp also suspected

Overdose

• Trimethoprim/sulfamethoxazole overdose can cause loss of appetite (anorexia), colic, nausea, vomiting, dizziness, headache, drowsiness, unconsciousness, high temperature (pyrexia), blood or crystals in the urine (hematuria or crystalluria). Blood disorders and jaundice are possible late manifestations of overdosage.
• Overdose may be treated with forced vomiting, gastric lavage, and acidification of urine to eliminate the undigested drug, and oral or intravenous fluids. Jaundice or blood disorders may be treated with treatments appropriate for the specific condition.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Trimethoprim/sulfamethoxazole has no known severe interactions with other drugs.
• Trimethoprim/sulfamethoxazole has serious interactions with at least 55 other drugs.
• Trimethoprim/sulfamethoxazole has moderate interactions with at least 190 other drugs.  
• Trimethoprim/sulfamethoxazole has mild interactions with at least 136 other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider about all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or healthcare provider if you have any questions about the medication.

• Trimethoprim/sulfamethoxazole may cause fetal harm if administered to pregnant women. Studies suggest that the drug is associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot.
• Untreated infections during pregnancy can result in adverse fetal outcomes including preterm birth, low birth weight, and adverse maternal outcomes that can include pre-eclampsia, and increased mortality.
• Trimethoprim/sulfamethoxazole should be used during pregnancy only if potential maternal benefits outweigh potential risks to the fetus.
• Trimethoprim/sulfamethoxazole is present in breastmilk. There is no information on the drug’s effects on milk production or the breastfed infant. Breastfeeding should be avoided during therapy because of the potential risk of bilirubin displacement, and associated brain damage (kernicterus) in the breastfed infant.

• Take trimethoprim/sulfamethoxazole exactly as prescribed.
• Complete the prescribed trimethoprim/sulfamethoxazole therapy; do not miss your oral doses or appointment for injections, or discontinue therapy if you feel better; it can decrease treatment effectiveness and lead to the development of drug-resistant bacteria.
• Drink adequate fluid while on treatment to prevent stone formation and urinary crystals.
• You will need periodic lab tests while on trimethoprim/sulfamethoxazole treatment. Follow up with your physician and do not miss your appointments.
• Inform your physician immediately if you develop hypersensitivity reactions to trimethoprim/sulfamethoxazole.
• Diarrhea is a common problem with antibiotic treatments which should resolve with the completion of the therapy. Seek medical help if you have watery or bloody stools, with or without stomach cramps and fever. Symptoms can develop even up to two months after the last dose of antibiotic.
• Store trimethoprim/sulfamethoxazole safely out of reach of children.
• In case of overdose seek medical help or contact Poison Control.